This renewal involves integrated synthetic, mechanistic, mode of action, computer modeling, biochemical, imaging and preclinical studies directed at the design, synthesis and advancement of fundamentally new leads and strategies for the treatment of cancer, HIV/AIDS and potentially other therapeutic indications. These studies focus on understanding the molecular basis for cellular signaling through protein kinase C (PKC) and related pathways relevant to cancer treatment and other indications;on the development of novel synthetic approaches to promising therapeutic leads, especially those that exhibit unique activity relevant to cancer;on the development of drug and probe transporters, including new linker methodology;and on a promising strategy for using transporters to overcome Pgp based cancer resistance. Section D.1 describes continuing studies on the synthesis and biological evaluation of gnidimacrin and its analogs, the former a potent anticancer lead with in vitro and in vivo activity and a novel mode of action putatively involving selective PKC ?-II regulation;at the elucidation of the structural basis for this novel activity and mode of action;and at the design of simplified and potentially clinically superior candidates. Section D.2 is directed at the synthesis of synaptolepis factor K7, kirkinine and related functional analogs - the former two being potent anti-leukemic leads;at elucidation of the structural basis for their activity;and at the design of simplified and more effective candidates for advancing research on and potential clinical use of these novel leads. Section D.3 is directed at the synthesis of prostratin and its functional analogs, the former an active constituent in a medicinal tea used by healers in Samoa and now in preclinical development for eradicating HIV/AIDS virus through latent virus activation, and at evaluation of the promising anticancer activity of the analogs, their role in PKC signaling, and their ability to purge the latent virus from HIV infected cells as a clinical approach to HIV eradication. Section D.4 is directed at the development of methodology for the synthesis of new releasable drug-transporter conjugates designed to evade cellular Pgp efflux pumps in drug-resistant cancer cell lines and release free drug upon cell entry, providing a potentially general strategy to overcome Pgp-based resistant cancer and more specifically an approach to treating resistant ovarian cancer. Section D.5 is directed at the development of novel oligomerization strategies for the synthesis of new molecular transporters for drug/probe delivery and evaluation of their performance in transfected cells and transgenic animals. Collectively, this program provides for the first synthetic access to several designed and natural compounds with unique activities, including promising therapeutic leads and two leads in preclinical development, one designed to overcome Pgp-based resistance in ovarian cancer and a second targeting HIV/AIDS latent virus and thus a potential adjuvant for virus eradication.
This project involves integrated synthetic, mechanistic, computer modeling, biochemical mode of action and preclinical studies directed at several promising anticancer leads including one that is also a clinical candidate for eradicating HIV/AIDS virus through latent virus activation, at the preclinical advancement of a novel strategy for overcoming resistant cancer, potentially applicable to ovarian cancer, and at the study of new drug delivery systems with potentially broad fundamental and clinical utility in cancer therapy and disease detection. The project seeks to advance our ability to synthesize molecules, at the same time to uncover new modes of action and strategies that are relevant to cancer therapy as well as other therapeutic indications, and to introduce new drug or probe delivery strategies for disease diagnosis and treatment. The project provides for the creation of fundamental knowledge of broad potential utility and at the same time new approaches and agents to address unmet clinical needs in cancer, HIV/AIDS and other diseases.
|Wender, Paul A; Inagaki, Fuyuhiko; Pfaffenbach, Magnus et al. (2014) Propargyltrimethylsilanes as allene equivalents in transition metal-catalyzed [5 + 2] cycloadditions. Org Lett 16:2923-5|
|Vargas, Jessica R; Stanzl, Erika Geihe; Teng, Nelson N H et al. (2014) Cell-penetrating, guanidinium-rich molecular transporters for overcoming efflux-mediated multidrug resistance. Mol Pharm 11:2553-65|
|Buehler, Daniel C; Marsden, Matthew D; Shen, Sean et al. (2014) Bioengineered vaults: self-assembling protein shell-lipophilic core nanoparticles for drug delivery. ACS Nano 8:7723-32|
|Wender, Paul A; Fournogerakis, Dennis N; Jeffreys, Matthew S et al. (2014) Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents. Nat Chem 6:448-52|
|Wender, Paul A; Nakagawa, Yu; Near, Katherine E et al. (2014) Computer-guided design, synthesis, and protein kinase C affinity of a new salicylate-based class of bryostatin analogs. Org Lett 16:5136-9|
|Wender, Paul A; Staveness, Daryl (2014) Improved protein kinase C affinity through final step diversification of a simplified salicylate-derived bryostatin analog scaffold. Org Lett 16:5140-3|
|Stanzl, Erika Geihe; Trantow, Brian M; Vargas, Jessica R et al. (2013) Fifteen years of cell-penetrating, guanidinium-rich molecular transporters: basic science, research tools, and clinical applications. Acc Chem Res 46:2944-54|
|Wender, Paul A (2013) Toward the Ideal Synthesis and Transformative Therapies: The Roles of Step Economy and Function Oriented Synthesis. Tetrahedron 69:7529-7550|
|Beans, Elizabeth J; Fournogerakis, Dennis; Gauntlett, Carolyn et al. (2013) Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo. Proc Natl Acad Sci U S A 110:11698-703|
|Wender, Paul A; Buschmann, Nicole; Cardin, Nathan B et al. (2011) Gateway synthesis of daphnane congeners and their protein kinase C affinities and cell-growth activities. Nat Chem 3:615-9|
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